Antibacterials

KEY POINTS

Increasing usage of antibacterials has selected for resistant strains of bacteria

Antimicrobial resistance is now a significant public health issue

Many of the antibacterials we use in veterinary practice are the same as those used in human medicine

We have a professional duty to use antibacterials responsibly and PROTECT the effectiveness for future use

The development of antibacterials has enabled many previously fatal diseases to be successfully treated and led to significant improvements in both human and animal health. However, as the increase in antibacterial resistance has become a significant public health issue, it is important that the veterinary profession uses antibacterials responsibly in order to:

Antibacterial resistance

Bacteria have developed various mechanisms to neutralize the action of antibacterial agents. Some bacteria are inherently resistant to certain antibacterials because of structural or functional characteristics (e.g. the medicine cannot cross the cell wall, the bacteria lack the medicine target, or they produce enzymes that destroy the medicine). This resistance is generally stable and well recognized (e.g. Pseudomonas spp. are inherently resistant to many antibacterials).

Bacteria may also acquire resistance through genetic changes in the bacterial genome or by genetic transfer. In these cases bacteria may acquire the ability to neutralize an antibacterial, or modify or replace the medicine target. It should be remembered that, because many currently used antibacterial medicines have been developed from naturally occurring antibiotics, bacteria have had a long time in which to develop these mechanisms. Multi-resistance can occur either when distinct genes confer resistance to different antibacterial classes (co-selection) or when a single gene confers resistance to two or more antibacterial agents (cross-selection).

Phenotypically, resistance may manifest in a wide variety of ways, including:

Production of enzymes that destroy the antibacterial agent

Production of efflux pumps, which prevent adequate accumulation of the antibacterial agent inside the bacterial cell

Mutation of the target site so that it is no longer recognized by the antibacterial agent.

With few exceptions, antibacterials do not induce resistance. Instead, resistance arises following random genetic mutations that change the cell structure, target molecule or metabolism of the antibacterial. Exposure to antibacterials favours survival of organisms carrying the resistance genes so that antibacterials exert selection pressure that allows the resistance genes to spread within the population. Selection pressure for antibacterial resistance is exerted on both pathogenic and commensal bacteria whenever an antibacterial is used.

Inherent resistance

This is the innate ability of a bacterial organism to resist the activity of a particular antimicrobial agent through its inherent structural or functional characteristics (see above).

Chromosomal resistance

It is estimated that 1 in 10,000,000 bacterial cells give rise to a daughter cell with a mutation. If this change confers antibacterial resistance in the organism through a change in the cell structure, target molecule or metabolism of the antibiotic it may provide a survival advantage in the face of antibacterial treatment.

Plasmid-mediated resistance

Once the genes for antibacterial resistance have appeared they can be passed on to other bacteria, not only by cell division but also by genetic transfer.

Guidance and regulations

UK Five Year Antimicrobial Resistance (AMR) Strategy 2013 to 2018

The AMR Strategy was drawn up by the UK’s Department of Health and Department for Environment, Food and Rural Affairs (Defra). The stated goal of the Strategy is to slow the development and spread of antimicrobial, including antibacterial, resistance. There are three strategic aims:

To improve the knowledge and understanding of antimicrobial resistance

To conserve and steward the effectiveness of existing treatments

To stimulate the development of new antibiotics, diagnostics and novel therapies.

The Strategy document indicates key areas for future action:

Improving infection prevention and control practices

Optimizing prescribing practice

Improving professional education and training in order to improve
clinical practice and promote wider understanding of the need for more
sustainable use of antibiotics

Better access to, and use of, surveillance data.

The Strategy document also states that veterinary surgeons and nurses, and their professional bodies, need to take action to improve the knowledge and understanding of antimicrobial resistance, and conserve the effectiveness of existing treatments by developing sector-specific prescribing guidelines and promoting responsible use practices. The full document can be viewed on the Government’s website. There is also a European Union action plan against antimicrobial resistance.

UK regulations and guidance on antimicrobial prescribing

The Royal College of Veterinary Surgeons (RCVS) has said that ‘The development and spread of antimicrobial resistance is a global health problem that is affected by both human and animal use of these medicinal products. Veterinary surgeons must be seen to ensure that when using antimicrobials they do so responsibly, and be accountable for the choices made in such use’.

The Veterinary Medicinal Products Directive 2001/82/EC (as amended) sets out controls on the manufacture, authorization, marketing, distribution and post-authorization surveillance of veterinary medicinal products (VMPs) in all European Member States. This directive is implemented in the UK through the Veterinary Medicines Regulations (VMR) which first came into force in October 2005 and are regularly updated. The current VMR and supporting guidance can be accessed on the Veterinary Medicines Directorate (VMD) website.

In September 2014, the European Commission adopted new proposals to replace the current Veterinary Medicinal Products Directive with a new European Regulation on VMPs. These proposals will now be considered by the European Parliament.

In the UK, all veterinary antibacterials are classified as ‘prescription-only medicines – veterinarian’ (POM-V), therefore the responsibility for and control of antibacterial use rests with the prescribing veterinary surgeon, who must first carry out a clinical assessment of the animal(s) under his or her care. However, as the VMR do not define the phrase ‘under his care’ the RCVS has interpreted it as meaning that:

a. The veterinary surgeon must have been given the responsibility for the health of the animal or herd by the owner or the owner’s agent

b. That responsibility must be real and not nominal

c. The animal or herd must have been seen immediately before the prescription; or

d. Recently enough or often enough for the veterinary surgeon to have personal knowledge of the condition of the animal or current health status of the herd or flock to make a diagnosis and prescribe

e. The veterinary surgeon must maintain clinical records of that herd/flock/individual.

The RCVS guidance goes on to say that what amounts to ‘recent enough’ must be a matter for the professional judgement of the vet in the individual case.

Guidance on adverse reactions

Adverse reactions are harmful and unintended reactions to a medicine when administered to an animal at the recommended dose and route of administration. Adverse reactions are normally considered in respect of the individual animal under treatment and include toxicity and treatment failure. In the case of an antibacterial agent this would include treatment failure despite culture and sensitivity results indicating that an appropriate antibacterial class was used, or where a particular product is authorized for the specific condition and species, and where the clinician’s experience would suggest that a positive response should have occurred.

Reports should be made to the Veterinary Medicines Directorate (VMD) using the Suspected Adverse Reaction Surveillance Scheme (SARSS) forms. These forms are available to download from the VMD website.

Prescribing antibiotics under the cascade

The VMD have issued a position statement entitled ‘Responsible antibiotic use under the cascade’, which states that the VMD considers that it is justified, on a case-by-case basis, to prescribe an antibiotic on the cascade in the interests of minimizing the development of resistance. This applies particularly where culture and sensitivity data indicate that a particular antibiotic active substance is effective against a bacterial pathogen and where knowledge of pharmacokinetics indicates that the selected product is likely to be safe and effective for the animal species and condition being treated (i.e. prescription of a narrow-spectrum antibiotic on the cascade over a broad-spectrum antibiotic that has a specific indication for that condition).

However, as with all prescribing decisions made under the cascade legislation, when selecting a VMP for a condition or species for which it is not authorized, ultimately the responsibility for that decision belongs to the veterinary surgeon, who should ensure that they are able to fully justify – using scientific evidence – their decision making process.

Veterinary access to critically important antimicrobials in humans

The World Health Organization (WHO) has developed a list of antimicrobial agents used in human medicine classified by importance. No antimicrobials in use were considered unimportant, and three categories were defined: critically important; highly important; and important. Antimicrobials were assigned to these categories based on two criteria:

Where the medicine is the sole therapy or one of few alternatives to treat serious human disease

Where the medicine is used to treat disease caused by organisms that may
be transmitted via non-human sources, or diseases caused by organisms
that may acquire resistance genes from non-human sources.

Antimicrobial medicines that meet both these criteria are classified as critically important, while those that only meet one of the criteria are classified as highly important. The current list can be accessed on the WHO’s website.

The World Organization for Animal Health (OIE) has produced a similar list of the antimicrobials considered important in veterinary medicine, which used the same categories of importance identified via slightly different criteria met:

When a majority of the respondents (more than 50%) identified the
importance of the antimicrobial class in their response to the
questionnaire

When compounds within the class were identified as essential against
specific infections and there was a lack of sufficient therapeutic
alternatives.

Unfortunately, many of the antibacterials that are relied on in veterinary medicine are considered critically important in human medicine, so veterinary surgeons have a duty to use them responsibly, not only to ensure their efficacy in the treatment of animal patients but also to endeavour to minimize the development of resistance to critically important human medicines. There are three categories of antibacterials that have been classified as ‘highest priority’ critically important antimicrobials and their use should receive particular consideration:

Quinolones

Third- and fourth-generation cephalosporins

Macrolides.

Responsible antibacterial prescribing

The responsible use of antimicrobials, according to the Heads of Medicines Agencies ‘…does not simply mean using less antimicrobials, it means justified use (based on a properly established diagnosis) of the most appropriate sensitive antimicrobial in a way optimising its clinical efficacy in the specific clinical cases and taking reasonable steps to ensure the method of use (including dose regime) applied help limit the potential for resistance to develop.’

There is no doubt that the use of antibacterials is frequently justified in the treatment of bacterial disease and leads to improvements in animal health and welfare. Treatment with a broad-spectrum highly potent relatively new antibacterial may be highly effective in the short term, but overuse will select for resistance and reduce usefulness in the medium to long term.

The rationale for the responsible use of antibacterial agents is to maximize therapeutic success and at the same time minimize the development of antibacterial resistance, thereby safeguarding antibacterials for future veterinary and human use. This can be done by reducing the unnecessary use of antibacterial agents and optimizing medicine choice, dose and dosing regimens. This requires that knowledge of clinical disease is integrated with knowledge of the pharmacology of antibacterial agents in order to inform clinical decision making.

The first decision to be made is whether antibacterial treatment is appropriate in a particular case; factors that may need to be taken into consideration are:

Does the condition necessitate antibacterial treatment?

Are there other options besides antibacterial treatment?

Will the potential risk of inducing resistance outweigh the benefit of treatment?

Is the proposed treatment likely to work against the pathogen involved?

Are there any risks to public health when this is done?

Once it has been decided that the use of antibacterials in a particular case is justified, it is important to select the antibacterial that is most likely to be effective based on the species being treated, the site of infection and knowledge of the bacteria likely to be involved. Where possible, it is better to use a narrow-spectrum rather than a broad-spectrum antibacterial to limit the effects on commensal bacteria. The veterinary surgeon can maximize the likelihood of therapeutic success and minimize the likelihood of selecting resistant bacteria by considering the following in their choice of antibacterial medicines:

The animal under treatment

The first consideration will be the species of animal under treatment as this will affect not only the diagnosis and organisms likely to be involved, but also the range of antibacterial medicines that are appropriate and available for treatment. Details of previous antibacterial medication can provide information about possible antibacterial resistance and current medication should lead to consideration of possible interactions. Co-morbidity, especially in terms of renal or hepatic conditions which may affect metabolism and elimination of medicines, should also be considered when selecting and appropriate antibacterial product.

Likely pathogenic organisms

The veterinary surgeon may have a good idea of the likely organism(s) involved in a particular condition. Some organisms have stable and predictable resistance patterns enabling rational antibacterial selection from empirical research and experience. However, it should be remembered that some bacteria have variable resistance patterns (e.g. Staphylococcus aureus, which may be methicillin-susceptible S. aureus (MSSA) or methicillin-resistant S. aureus (MRSA)). Other bacteria, such as Escherichia coli and Pseudomonas, are known to have unpredictable resistance patterns, which are likely to require culture and sensitivity testing to be undertaken to establish antibacterial susceptibility. Clinical resistance (whether the antibacterial will or will not work in a patient) is a more complex concept in which many other factors are involved, such as the precise location of the infection, the distribution of the medicine in body fluids and the state of the patient’s immune system.

Distribution

In order to assess the ability of the antibacterial to reach the site of infection at an appropriate concentration, the veterinary surgeon needs a working knowledge of the pharmacokinetics of the antibacterial, in particular knowledge of its distribution.

Severity of the infection

The severity of the infection may determine the need to start antibacterial treatment before culture and sensitivity results are obtained. In these cases, it may be appropriate to start broad-spectrum antibacterial therapy, possibly using a combination of medicines while awaiting results. Combinations can be particularly useful if there is a mixed infection (e.g. an aminoglycoside (Gram-negative spectrum) with clindamycin (anaerobic spectrum)). Combinations may also be indicated for agents where resistance develops rapidly, so rapid antibacterial killing is desirable.

Spectrum of activity

Veterinary surgeons should have a working knowledge of the spectrum of activity of the main antibacterials used in veterinary practice. In order to minimize resistance, veterinary surgeons should opt for the narrowest spectrum agent. For example:

a. Anaerobic infections: metronidazole; clindamycin; many of the penicillins and cephalosporins (especially the narrow-spectrum penicillins such as Penicillin G)

The PROTECT message developed out of an initiative of the Small Animal Medicine Society (SAMSoc) to review and promote responsible antibacterial prescribing. This led to the PROTECT poster, produced by BSAVA and SAMSoc.

The PROTECT message is that antibacterials need to be used responsibly – therefore, before they are prescribed, the following should be considered:

Practice policy?

A practice policy for empirical prescribing (whilst awaiting cultures) can optimize therapy and minimize inappropriate use of antibacterials. The PROTECT poster can provide a useful reminder of practice prescribing policy.

Reducing prophylaxis?

Antibacterials are not a substitute for surgical asepsis and the need for prophylactic antibacterials in surgery should be carefully considered. Prophylactic antibacterials are only appropriate in a few medical cases (e.g. in immunocompromised patients).

Other options for treatment?

Before prescribing antibacterials it is worth considering whether there are other options.

Types of bacteria and medicine?

Before prescribing antibacterials, the following should be considered:

Which bacteria are likely to be involved (e.g. anaerobic/aerobic, Gram-positive/Gram-negative)

The distribution and penetration of the medicine

Any potential side effects.

Employing the correct antibacterial?

Where possible it is better to use a narrow-spectrum rather than a broad-spectrum antibacterial, to limit the effects on commensal bacteria.

Cytology and culture?

Use cytology and culture to diagnose bacterial infection correctly. Culture is not required in every case, but when prolonged courses of antibacterials are likely to be needed (e.g. pyoderma, otitis externa, deep or surgical wounds, or following failure of empirical dosing), culture first, ask questions later!

Treating effectively?

In order to treat effectively, it is necessary to:

Treat for long enough and at a sufficient dose to kill the bacteria, and then stop

Avoid under-dosing and consider how the medicine will penetrate the target area

Repeat culture after long courses of antibacterials.

Development of practice guidelines

Antibacterial prescribing is a common part of practice and many, though not all, of the conditions treated are common. It may also be appropriate to consider guidelines about when antimicrobials should (or should not) be prescribed, when it is appropriate to make empirical decisions (e.g. the first presentation of pyoderma or uncomplicated urinary tract infections) and when cytology or culture and sensitivity tests should be undertaken. It may be appropriate to consider the duration of treatment and frequency of checks that would be expected in uncomplicated cases. The practice may also agree guidelines on the use of antibacterials in surgical prophylaxis.

Taking time to institute practice-based guidelines for antibacterial use should be considered. These guidelines should take account of the:

Animals that are commonly treated in the practice

Conditions that are commonly encountered

Causal organisms that are likely to be involved in particular
conditions, with cytology or culture being use to provide confirmation
where appropriate

Antibacterials to which they are most likely to be sensitive.

It can be useful to start by creating a table of first-, second- and third-choice antibacterials:

First-choice antibacterials would comprise agents appropriate for
initial treatment, not necessarily based on culture and sensitivity

Second-choice antibacterials should be prescribed on the basis of
culture and sensitivity data, where no first-choice agents are
appropriate

Third-choice antibacterials should only be prescribed for serious and
life-threatening infections, based on culture and sensitivity data, and
only where no first- or second-choice agents are appropriate.

Certain antimicrobials should be used judiciously. This means that their use as first-choice agents should be avoided, and they should only be used when other agents are ineffective (ideally determined by culture and sensitivity testing). These include:

Fluoroquinolones

Third- and fourth- generation cephalosporins

Amikacin.

Certain antimicrobials should probably not be used in veterinary species. These are agents of last resort in human patients and include:

Vancomycin

Carbapenems such as imipenem.

The PROTECT poster produced by BSAVA and SAMSoc can provide a useful method of recording the agreed practice policy.

Prophylactic antibacterial use

Prophylactic antibacterial use is the administration of antibacterials in the absence of infection, with the aim of preventing it. The most common reason for the prophylactic use of antibacterials in small animal veterinary practice is in the perioperative period, but their use may also be appropriate in certain medical situations; for example, when an animal is considered to be at increased risk due to concurrent disease or immunosuppressive therapy and is in contact with other infected animals.

Ideally, the prophylactic use of antibacterials should be based on careful risk assessment. It is important for any risk assessment to balance the risks of developing infections in the individual animal with the risk of selecting for resistance bacteria.

Surgical prophylaxis

Prophylactic antibacterial use may be appropriate in the perioperative period, although it should not be a substitute for good asepsis. The perioperative use of antibacterials can reduce the incidence of postoperative surgical site infection, but where the risk is low inappropriate use of antibacterials is most likely to result in unnecessary costs for the owner and can increase the occurrence of antibacterial resistance and super-infection. It should be remembered that surgical site infection is most likely to arise from colonization of the wound by the animal’s own endemic flora and the inappropriate use of perioperative antibiotics may increase the risk of surgical site infection with opportunistic organisms, which are more difficult to treat.

Examples of appropriate criteria for perioperative antibacterial use include:

Prolonged surgical procedures (>1.5 hours)

Introduction of an implant into the body

Procedures where introduction of infection would be catastrophic (e.g. central nervous system surgery)

Where there is an obvious identified break in asepsis

Bowel surgery with a risk of leakage

Dentistry with associated periodontal disease

Contaminated wounds.

To be effective, prophylactic antibacterials at appropriate concentrations must be present in tissues at the surgical site at the time of contamination to prevent bacterial growth and subsequent infection.

Administer the first dose 1 hour before the incision

Re-administer during surgery if the procedure is ongoing after two half-lives of the medicine have passed

Restrict treatment to the duration of the surgery or less than 24 hours,
except where therapeutic doses are required (e.g. gross contamination,
pre-existing infection)

Avoid the use of newer broad-spectrum antibacterials.

For further details of surgical asepsis, see the BSAVA Manual of Canine and Feline Surgical Principles.

Immunocompromised patients

Patients may be immunocompromised for a number of reasons including chemotherapy. Mild neutropenia is common and often not a clinical problem, but severe neutropenia can be complicated by sepsis and can be life threatening. Current guidelines in human oncology recommend avoiding the routine use of antibacterial prophylaxis because of concerns of emerging medicine-resistant bacteria. Therefore, it would seem prudent to adopt similar measures in veterinary species and only use antibacterial prophylaxis in patients receiving chemotherapy if the neutrophil count is <1 x 10 9/l (1000 neutrophils/μl).

Alternatives to antibacterials

Infection control including reducing the need for prophylactic use of antibacterials in clean surgery

Accurate diagnosis and restriction of the use of antibacterials to those
cases where it is known or strongly suspected that the disease is
caused by bacteria

Consideration of alternative treatments.

One of the best ways of protecting the effectiveness of antibacterials is to use them sparingly. This means that veterinary surgeons may need to consider other options when faced with bacterial infections in patients.

Before prescribing antibacterials, it may be worth considering the following:

Not all animals with bacterial infections require antibacterial
treatment. In healthy individuals, reducing the bacterial load may be
sufficient to enable recovery. The use of antiseptic washes and ear
cleaners may reduce the need for antibacterials in pyoderma and otitis
externa, respectively

Effective lavage and debridement of infected material reduces the need
for antibacterials. Antiseptics and antibacterial wound dressings also
reduce the need for systemic antibacterials

The use of topical prescriptions reduces selection pressure on resistant intestinal flora

Rectifying the underlying cause of disease may reduce the need for antibacterial treatment.

Culture and sensitivity testing

Sampling for bacterial disease is common in veterinary practice and can give information that aids in the rational selection of antibacterial treatment. Culture and sensitivity test results considerably assist the choice of which antimicrobial to use. Culture is not required in every case, but when prolonged courses of antimicrobials are likely to be needed (e.g. pyoderma, otitis externa and deep or surgical would infections) or when there is uncertainty about the presence or sensitivity of a bacterial infection then culture and sensitivity testing will improve the animal’s treatment.

Direct microscopy of smears

This is a useful but underutilized tool in the initial investigation of an infection. It can enable:

Detection of bacteria and other microorganisms

Determination of bacterial morphology (cocci or rods, streptococci or staphylococci) and Gram staining

Prediction of the identification of microorganisms detected

Appropriate selection of empirical antibacterial treatment in the
absence of or while awaiting culture and sensitivity test results.

Samples for bacteria culture

Taken from live animals as early as possible and before antibacterial treatment commences

Taken carefully to minimize contamination

Appropriate in type and quantity to the type of culture required

Taken into the correct transport medium to maximize bacterial survival

Packaged appropriately in accordance with Health and Safety requirements

Kept at room temperature and dispatched for culture within 24 hours wherever possible.

The isolation of bacteria from an animal is not proof of pathogenicity; the normal bacteria for the species and sample examined should be considered when assessing their significance.

In vitro testing

This is indicated for any bacterial pathogen when the susceptibility cannot be reliably predicted and/or the organism is capable of developing resistance to antibacterial medicines.

Agar gel disc diffusion – a uniform suspension of the bacterium under
investigation is spread across an agar gel plate and paper discs
impregnated with a known concentration are added. The plate is then
incubated. If the bacterium incubated is sensitive to a particular
antibacterial medicine, a zone of inhibition occurs around the disc.
Zone diameters are compared to standard figures to decide whether the
bacterium is sensitive or resistant to a particular antibacterial
medicine.

E-test strip – a variation in which a strip containing gradations of
medicine concentration is placed on the surface. Following incubation
the point on the strip that intersects with the line of bacterial
inhibition is recorded as the minimum inhibitory concentration (MIC).

Broth dilution MIC – the lowest concentration of an antibiotic that
inhibits the growth of the bacterium under test. MICs are determined by
inoculating a bacterial isolate into a series of test wells with
doubling dilutions of the antibacterial medicine under test. The test
provides information on the antibacterial concentrations at which the
bacterium is able to grow or is inhibited.

The MIC is the lowest medicine concentration inhibiting the growth of the bacterial inoculum. These results are interpreted in the light of likely serum concentrations of antibacterial to describe the bacterium as sensitive or resistant to a particular antibiotic, with the breakpoint being determined by the medicine’s in vitro activity, achievable medicine concentrations in the host, distribution and elimination data and medicine toxicity. Bacteria described as having an intermediate sensitivity may be sensitive where the antibacterial can safely be given in high doses or at sites in the body where the antibacterial medicine is concentrated.

Rational antibacterial combinations

The most commonly used combinations in companion animal practice are potentiated amoxicillins, where potassium clavulanate is used to extend the spectrum of activity through the inhibition of beta-lactamase, and trimethoprim, a tetrahydrofolate inhibitor, which has a synergistic effect with sulphonamides leading to bactericidal activity and reducing required dosage. Both of these may be regarded as rational choices and advantageous in reducing the likelihood of resistance emerging.

Combinations may be useful if there is a mixed infection (e.g. an
aminoglycoside (Gram-negative spectrum) with clindamycin (anaerobic
spectrum)).

Synergism is described for some combinations (e.g. aminoglycosides
combined with penicillins or sulphonamides combined with
diamiopyrimidines).

Do not combine a bactericidal with a bacteriostatic antibacterial as an antagonistic effect occurs.

2. Which of the following adverse reactions should be reported to the VMD?

a. Apparent toxicity of a veterinary authorized productb. Antibacterial treatment failurec. Human reaction to a veterinary productd. All of the above

3. In developing a practice policy on antibacterial use, which of the following should be taken into consideration?

a. The animals that are commonly treated, and the conditions commonly encountered, in the practiceb. The causal organisms that are likely to be involved in particular conditions, with cytology or culture being used to provide confirmation where appropriatec. The antibacterials to which they are most likely to be sensitived. All of the above